Namenda

Before using memantine, tell your doctor if you are allergic to any drugs, or if you have a seizure disorder, cataracts, liver or kidney disease, or a bladder or kidney infection.

Memantine can cause side effects that may impair your thinking or reactions. Be careful if you drive or do anything that requires you to be awake and alert.

• The recommended starting dose of Namenda is 5 mg once daily. The recommended target dose is 20 mg/day. The dose should be increased in 5 mg increments to 10 mg/day (5 mg twice a day), 15 mg/day (5 mg and 10 mg as separate doses), and 20 mg/day (10mg twice a day).

In case of overdose, call your local poison control center. If the victim has collapsed or is not breathing, call local emergency services at 911. Symptoms of overdose may include:

• restlessness 
• hallucination (seeing things or hearing voices that do not exist) 
• sleepiness 
• loss of consciousness 

Because strategies for the management of overdose are continually evolving, it is advisable to contact a poison control center to determine the latest recommendations for the management of an overdose of any drug.

N-Methyl-d-aspartate (NMDA) receptor antagonist.1 2 3 4 5 6 7 8 9 10 11 12 13

Minimally metabolized by CYP isoenzymes.1 Memantine produces minimal inhibition of isoenzymes 1A2, 2A6, 2C9, 2D6, 2E1, or 3A4 in vitro.1 No induction of isoenzymes 1A2, 2C9, 2E1, or A4/5 observed in vitro at concentrations exceeding those associated with therapeutic efficacy.1

Drugs Affecting Hepatic Microsomal Enzymes

Pharmacokinetic interactions unlikely.1 15

Drugs Metabolized by Hepatic Microsomal Enzymes

Pharmacokinetic interactions unlikely.1

Alkalinizing Agents

Potential decreased memantine clearance with resulting increases in adverse effects when the drug is used concomitantly with agents that increase urine pH.1 Use with caution.1

Protein-bound Drugs

Pharmacokinetic interaction with highly plasma protein-bound drugs is unlikely because memantine is only 45% bound to plasma proteins.1

Drugs Secreted by Renal Tubular Cationic Transport

Potential pharmacokinetic interaction (altered plasma concentrations of both drugs) when used with drugs secreted by the same renal cationic system.10

Specific Drugs

Absorption

Well absorbed following oral administration, with peak plasma concentrations attained in about 3–7 hours.1 4

Tablets and oral solution are equivalent on a mg-per-mg basis.15

Food

Food does not appear to affect absorption.1

Distribution

Extent

Not known whether memantine is distributed into human milk.1

45%.1

Elimination

Metabolism

Undergoes limited metabolism, principally to 3 inactive metabolites; minimally metabolized by CYP isoenzymes.1

Elimination Route

Excreted principally in urine as unchanged drug (57–82%).1

Eliminated via active tubular secretion, moderated by pH-dependent tubular reabsorption. Clearance reduced by about 80% under alkaline urine conditions (urine pH of 8).

Half-life

Terminal half-life is approximately 60–80 hours.1

Special Populations

In patients with hepatic impairment, only a modest effect on clearance is expected.1

Renal impairment increases exposure.1 AUC increased by 4, 60, or 115% in individuals with mild (Clcr >50 but <80 mL/minute), moderate (Clcr 30–49 mL/minute), or severe (Clcr 5–29 mL/minute) renal impairment, respectively.1 Terminal elimination half-life increased by 18, 41, or 95% in those with mild, moderate, or severe renal impairment, respectively.1 (See Renal Impairment under Dosage and Administration and under Cautions.)

In geriatric patients, pharmacokinetics similar to those in younger adults.1

Namenda 5 mg tablet: capsule-shaped, film-coated tablets are tan, with the strength (5) debossed on one side and FL on the other.

Namenda 10 mg tablet: capsule-shaped, film-coated tablets are gray, with the strength (10) debossed on one side and FL on the other.

Namenda 2 mg/mL oral solution: clear, alcohol-free, sugar-free, and peppermint flavored.

Clinical Trials Experience

Namenda was evaluated in eight double-blind placebo-controlled trials involving a total of 1862 dementia (Alzheimer's disease, vascular dementia) patients (940 patients treated with Namenda and 922 patients treated with placebo) for a treatment period up to 28 weeks.

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice.

Adverse Events Leading to Discontinuation

In placebo-controlled trials in which dementia patients received doses of Namenda up to 20 mg/day, the likelihood of discontinuation because of an adverse reaction was the same in the Namenda group (10.1%) as in the placebo group (11.5%). No individual adverse reaction was associated with the discontinuation of treatment in 1% or more of Namenda-treated patients and at a rate greater than placebo.

Most Common Adverse Reactions

In double-blind placebo-controlled trials involving dementia patients, the most common adverse reactions (incidence ≥ 5% and higher than placebo) in patients treated with Namenda were dizziness, headache, confusion and constipation. Table 1 lists all adverse reactions that occurred in at least 2% of patients treated with Namenda and at an incidence greater than placebo.

The overall profile of adverse reactions and the incidence rates for individual adverse reactions in the subpopulation of patients with moderate to severe Alzheimer's disease were not different from the profile and incidence rates described above for the overall dementia population.

Seizures

Namenda has not been systematically evaluated in patients with a seizure disorder. In clinical trials of Namenda, seizures occurred in 0.2% of patients treated with Namenda and 0.5% of patients treated with placebo.

Postmarketing Experience

The following adverse reactions have been identified during post-approval use of memantine. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. These reactions include:

Blood and Lymphatic System Disorders - agranulocytosis, leukopenia (including neutropenia), pancytopenia, thrombocytopenia, thrombotic thrombocytopenic purpura.

Cardiac Disorders - cardiac failure congestive.

Gastrointestinal Disorders - pancreatitis.

Hepatobiliary Disorders – hepatitis.

Psychiatric Disorders - suicidal ideation.

Renal and Urinary Disorders - acute renal failure (including increased creatinine and renal insufficiency).

Skin Disorders - Stevens Johnson syndrome.

Pregnancy

Pregnancy Category B

There are no adequate and well-controlled studies of memantine in pregnant women. Namenda should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Memantine given orally to pregnant rats and pregnant rabbits during the period of organogenesis was not teratogenic up to the highest doses tested (18 mg/kg/day in rats and 30 mg/kg/day in rabbits, which are 9 and 30 times, respectively, the maximum recommended human dose [MRHD] on a mg/m2 basis).

Slight maternal toxicity, decreased pup weights and an increased incidence of non-ossified cervical vertebrae were seen at an oral dose of 18 mg/kg/day in a study in which rats were given oral memantine beginning pre-mating and continuing through the postpartum period. Slight maternal toxicity and decreased pup weights were also seen at this dose in a study in which rats were treated from day 15 of gestation through the postpartum period. The no-effect dose for these effects was 6 mg/kg, which is 3 times the MRHD on a mg/m2 basis.

Nursing Mothers

It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when Namenda is administered to a nursing mother.

Pediatric Use

Safety and effectiveness in pediatric patients have not been established.

Geriatric Use

The majority of people with Alzheimer's disease are 65 years and older. In the clinical studies of Namenda the mean age of patients was approximately 76; over 90% of patients were 65 years and older, 60% were 75 years and older, and 12% were at or above 85 years of age. The efficacy and safety data presented in the clinical trial sections were obtained from these patients. There were no clinically meaningful differences in most adverse events reported by patient groups ≥65 years old and <65 year old.

Renal Impairment

No dosage adjustment is needed in patients with mild or moderate renal impairment. A dosage reduction is recommended in patients with severe renal impairment [see Dosage and Administration (2) and Clinical Pharmacology (12.3)].

Hepatic Impairment

No dosage adjustment is needed in patients with mild or moderate hepatic impairment. Namenda should be administered with caution to patients with severe hepatic impairment [see Dosage and Administration (2) and Clinical Pharmacology (12.3)].

Get emergency medical help if you have signs of an allergic reaction to Namenda: hives; difficulty breathing; swelling of your face, lips, tongue, or throat.

Call your doctor at once if you have:

• severe headache, blurred vision, pounding in your neck or ears;

• seizure (convulsions); or

• unusual changes in mood or behavior.

Common Namenda side effects may include:

• diarrhea;

• dizziness; or

• headache.

This is not a complete list of side effects and others may occur. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

Applies to memantine: oral capsule extended release, oral solution, oral tablet

Along with its needed effects, memantine (the active ingredient contained in Namenda) may cause some unwanted effects. Although not all of these side effects may occur, if they do occur they may need medical attention.

Check with your doctor immediately if any of the following side effects occur while taking memantine:

• Bloating or swelling of the face, arms, hands, lower legs, or feet
• blurred vision
• dizziness
• headache
• nervousness
• pounding in the ears
• rapid weight gain
• slow or fast heartbeat
• tingling of the hands or feet
• unusual weight gain or loss

• Abdominal or stomach pain
• agitation
• black, tarry stools
• bleeding gums
• blistering, peeling, or loosening of the skin
• blood in the urine or stools
• chest pain
• coma
• constipation
• continuing vomiting
• convulsions
• dark-colored urine
• decreased urine output
• depression
• fainting
• fast, pounding, or irregular heartbeat or pulse
• general feeling of tiredness or weakness
• high fever
• high or low blood pressure
• hostility
• increased sweating
• indigestion
• infection from breathing foreign substances into the lungs
• itching
• lethargy
• light-colored stools
• lip smacking or puckering
• loss of consciousness
• muscle twitching
• no blood pressure
• no breathing
• no pulse
• numbness or tingling in the face, arms, or legs
• pain in the stomach, side, or abdomen, possibly radiating to the back
• pain or swelling in the arms or legs without any injury
• pain, tension, and weakness upon walking that subsides during periods of rest
• pinpoint red spots on the skin
• pounding, slow heartbeat
• puffing of the cheeks
• rapid or worm-like movements of the tongue
• rapid weight gain
• recurrent fainting
• red irritated eyes
• red skin lesions, often with a purple center
• seizures
• severe constipation
• severe headache
• severe muscle stiffness
• severe vomiting
• sores, ulcers, or white spots in the mouth or on the lips
• stupor
• sudden severe weakness
• swelling of the face, ankles, or hands
• total body jerking
• trouble with speaking or walking
• troubled breathing
• twitching, twisting, or uncontrolled repetitive movements of the tongue, lips, face, arms, or legs
• uncontrolled chewing movements
• unusual bleeding or bruising
• unusually pale skin
• vomiting
• yellow eyes and skin

Some side effects of memantine may occur that usually do not need medical attention. These side effects may go away during treatment as your body adjusts to the medicine. Also, your health care professional may be able to tell you about ways to prevent or reduce some of these side effects. Check with your health care professional if any of the following side effects continue or are bothersome or if you have any questions about them:

• Confusion

• Anxiety
• back pain
• bladder pain
• bloody or cloudy urine
• change in walking and balance
• chills
• clumsiness or unsteadiness
• cough producing mucus
• coughing
• diarrhea
• difficult, burning, or painful urination
• difficulty with breathing
• difficulty with moving
• discouragement
• dry mouth
• fear
• feeling sad or empty
• fever
• frequent urge to urinate
• general feeling of discomfort or illness
• hyperventilation
• insomnia
• irritability
• joint pain
• loss of appetite
• loss of bladder control
• loss of interest or pleasure
• lower back or side pain
• muscle pain or stiffness
• nausea
• nervousness
• pain
• pain in the joints
• restlessness
• seeing, hearing, or feeling things that are not there
• shortness of breath
• sleepiness or unusual drowsiness
• sore throat
• tightness in the chest
• tiredness
• trouble with concentrating
• trouble with sleeping
• unusual tiredness or weakness
• vomiting
• wheezing

• Burning feeling in the chest or stomach
• burning, numbness, pain, or tingling in all fingers except smallest finger
• cold sweats
• cool pale skin
• decreased interest in sexual intercourse
• difficulty with swallowing
• general feeling of discomfort or illness
• heartburn
• inability to have or keep an erection
• increased hunger
• large amounts of fat in the blood
• loss in sexual ability, desire, drive, or performance
• nightmares
• shakiness
• slurred speech
• stomach cramps
• stomach upset
• tenderness in the stomach area
• watery or bloody diarrhea